The unprecedented advances made in current understanding of the molecular origins of cancer have not translated into a commensurate decrease in mortality from metastatic disease. In our judgment, a more complete understanding of the integrative biology of metastasis is essential for the development of novel and effective approaches to cancer treatment. In this Bioengineering Research Partnership program, we use a systems approach to uncover molecular, cellular and physical mechanisms governing metastasis, and we use mathematical modeling to integrate the results. To this end, we have built a multidisciplinary team of Harvard-MGH bioengineers, tumor biologists and clinicians (as well as 30 collaborative partners) with a successful track record of integrative basic and translational investigations. Results from this team over the past 3.5 years led to novel bioengineering innovations, a comprehensive mathematical model of cell bio-distribution and exciting scientific findings that suggest compelling new hypotheses regarding tumor-host interactions and metastases. Specifically, in Project 1 (D. Fukumura, MD, PhD), we revisit the century old "seed and soil hypothesis" and suggest a new paradigm for the role of stromal cells in metastasis. In Project 2 (Y. Boucher, PhD), we aim to explain the important clinical observation that defects in collagen synthesis correlate with increased metastasis, and to identify new therapeutic targets in the collagen matrix. In Project 3 (L.L. Munn, PhD), we investigate effects of mechanical stress on tumor progression and metastasis - an important yet unexplored area of research. Finally, in Project 4 (R.K. Jain, PhD), we utilize a clinically relevant model of distant disease to control both lymphatic and blood-borne metastases by blocking VEGFR1, -R2 and -R3 pathways. These four projects draw on shared bioengineering, imaging, mathematical modeling, and statistical support provided by Core A; molecular, cellular and histological capabilities provided by Core B; surgical support provided by Core C; and administrative support provided by Core D. In addition to our established techniques for molecular and functional imaging, we recently developed powerful multi-photon microscopy techniques that provide stunning insight in vivo at molecular and cellular resolution. We expect to realize the proposed goals using this technology, in combination with novel animal models, molecular biology tools and mathematical models of cell biodistribution. Finally, we have the resources and the clinical collaborators in place to initiate a clinical trial based on our findings, as attested by our ongoing trial using a VEGF-specific antibody.